光声成像从原理上避开了生物组织对光的强散射，突破了传统光学技术的成像深度极限。以跨尺度在体光声成像为主线，申报人在光声显微、内窥、分子影像领域，先后研发多个创新的技术和系统，奠定了亚细胞到器官跨尺度光声成像的基础，为研究肿瘤精准诊疗提供了革新的工具，有力推进了光声技术的临床和产业转化。以第一或通讯作者发表SCI一区期刊论文17篇，被Science等顶尖期刊多次引用及高度评价；两次入选美国光学学会的最多下载及亮点论文，获专文正面评论。申请专利20余项，两项转化到企业。基于前期工作，本课题拟通过水浸MEMS振镜光-声共轴扫描等技术创新，解决单一光声系统跨尺度成像无法兼顾速度、灵敏度、视场的重要矛盾，研制全新的跨尺度、多参量光声成像系统。实现活体状态下肿瘤血管形态、功能、分子活动等重要参量的全面获取，为开辟依托血管正常化的肿瘤治疗新途径，提供新思路。本课题在技术和应用上，都是前期研究的高度升华。

Photoacoustic imaging (PAI) has broken through the optical diffusion limit (~1 mm) and enabled the visualization of intact biological tissue in vivo at unprecedented depths (up to 7 cm) with rich optical contrasts. As a result, photoacoustic imaging can provide anatomic, functional, and molecular information on biological tissue at multiple length scales from organelles to organs. During the past few years, focusing on achieving multiscale PAI as the ultimate goal, the applicant has developed a series of innovative technologies; published 17 high-quality SCI-indexed articles in JCR Q-1 journals, as first- or corresponding-author; filed >20 invention patents, with two licensed to the industry. Some representative accomplishments include: (1) Invented in vivo reflection-mode photoacoustic microscopy with a spatial resolution of 320 nm, opening up new avenues for sub-cellular biomedical imaging (top downloads and highlighted by OSA as Spotlight on Optics); (2) Developed a first-of-its-kind photoacoustic endomicroscope for high-resolution imaging of internal organs (e.g., the heart and GI tract) (technology licensed to industry; results cited by JACC); (3) Developed multiple novel high-speed PAI technologies and molecular probes for cancer theranostics and sentinel lymph node mapping (results cited by Science, Nature Medicine etc.). These previous studies have significantly contributed to the biomedical imaging field and greatly facilitated the clinical translation and commercialization of PAI. ..In this proposed research, building on our previous work, we aim to develop a truly multi-scale, multi-parametric PAI system that integrates optical- and acoustic-resolution PAI into one single system. We will adopt and develop a number of novel technologies and designs, such as water-immersible MEMS mirror based fast optical-acoustic co-axial scanning, to break through the long-standing challenges in this regime, including the serious trade-off among the speed, sensitivity, and field of view. Using this system, together with the development of sophisticated signal processing algorithms, we will be able to simultaneously extract the morphology, functional, and molecular information for quantifying tumor vascular normalization. While the development of new cancer therapeutic strategies under tumor vascular normalization (TVN) has been rapidly emerging as a new opportunity to fight cancer, there are still many unknowns critical to the ultimate success. Hence, the developed PAI system is expected to offer new insights into TVN, and will be of enormous value for guiding the exploration of novel cancer therapy strategies combining conventional chemotherapy with TVN. In the conclusion of this research, we expect to have: (1) a validated multi-scale PAI system that may become a new vital imaging tool for many biomedical applications; (3) established guidelines for PAI of TVN; (4) new insights into the development of novel cancer therapeutic strategies based on TVN.